Staphylococcus aureus is an opportunistic bacterial pathogen responsible for a diverse spectrum of human and animal diseases. The bacterium may asymptomatically colonize epithelial surfaces, but it also has the invasive potential to cause severe infections, including osteomyelitis, endocarditis, and bacteremia with metastatic complications. The anterior nares serve as a major reservoir of Staphylococcus aureus in humans, and approximately 80 percent of the population are persistent or intermittent carriers. Carriage is a risk factor for S. aureus infection in a number of susceptible populations, including surgical and dialysis patients. Attenuation of carriage with the antibiotic mupirocin has been shown to reduce the prevalence of infection in certain high-risk groups. Since little is known about the host and bacterial factors involved in S. aureus nasal colonization, a mouse model of nasal carriage was developed to study these factors. The overall goal of this study is to utilize this animal model to determine whether the expression of staphylococcal surface antigens influences the establishment of colonization. The mouse nasal colonization model will also be utilized to determine whether mucosal immunization with S. aureus surface antigens can prevent nasal colonization in naive animals. Specific aim 1 is directed at reducing the inoculum needed to establish colonization by utilizing young mice (1 to 4 wks of age) rather than adult mice (6 to 7 wks of age). Under specific aim 2, the role of S. aureus surface antigens in establishing nasal colonization in mice will be assessed. Mutants defective in serotype 5 and 8 capsule expression will be compared with the parental strains for their ability to colonize the nares of mice. Likewise, well-characterized mutants defective in staphylococcal adhesins will be compared with the parental strains for their ability to colonize the nares of mice. Specific aim 3 will determine whether antibodies to S. aureus whole bacteria, capsular polysaccharides, or adhesins will prevent establishment of staphylococcal nasal carriage in mice. Mice will be actively immunized by the subcutaneous or intranasal route or passively immunized intraperitoneally with normal or immune serum antibodies. The results of this study may identify the bacterial factors that promote colonization and reveal potential targets for eliminating S. aureus nasal carriage.